Devices and methods for treatment of tumors using electromagnetic signal

ABSTRACT

Systems and methods for treating cancerous tumors (including glioblastoma multiforme (GBM)) with electrotherapy, such as deep brain stimulation (DBS) technology, as disclosed herein. One or more configurations can be generated based on a patients tumor characteristics. The selected configurations can be electrode configurations or settings for an electrical source coupled to the electrodes. The one or more configurations can be targeted for inhibiting cell growth process, such as to inhibit mitosis, immune suppression, or to inhibit DNA replication. Inhibition of cell growth processes can initiate death of the cancerous cells.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 17/250,735, filed on Feb. 26, 2021, which is a National Phaseentry of PCT Application No. PCT/US2019/048858, filed Aug. 29, 2019,which claims the benefit of U.S. Provisional Application No. 62/724,177filed Aug. 28, 2018, all of which are hereby incorporated herein in itsentirety by reference.

TECHNICAL FIELD

Embodiments relate to devices and methods for the treatment of cancerousor other tissues having different response to electrical stimuli basedupon their physical properties as compared to surrounding, healthy ornon-cancerous tissues.

BACKGROUND

Current cancer treatments rely on compounds and methodologies that aregenerally toxic or damaging to human tissues and cells. These treatmentsare often equally, if not more, dangerous to healthy tissue and cellsthan they are to the cancer. Evidence that tumor cells fail to thriveunder the effects of an electric field allows for the development oftreatment which will preferentially attack tumor cells, leaving healthytissue unaffected. The brain, and more generally the central nervoussystem, is ideal for such a treatment, due to the pronounced differencebetween the characteristics of a Central Nervous System (CNS) neuron andthose of a tumor cell. In particular, the static nature of a matureneuron protects the healthy cells from many effects to which the rapidlydividing tumor cells are vulnerable.

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor. Theprognosis of a patient with GBM is extremely poor, with nearly uniformfatality within two years of diagnosis. GBM is the most common form ofbrain cancer, affecting both men and women of any age. The incidencerate of GBM tumors is approximately 3 in 100,000 per year in the UnitedStates, or about 10,000 new cases each year. There are about 64,000 newtumors of the central nervous system and 17,000 primary brain tumorsdiagnosed in the United States each year.

Efforts to improve the prognosis of GBM patients have had littlesuccess. Standard treatment for GBM includes surgical resection,whenever possible. Such treatment is difficult because GBM tumors aregenerally invasive and located in areas of the brain that control thesenses, motor function, and speech. Surgical resection is then followedby radiotherapy and chemotherapy. These treatments are harmful tohealthy brain tissue adjacent to the treated area, which further limitsthe efficacy of treatment via radiotherapy.

Further, these techniques are not curative due to the invasiveness ofthe tumor. GBM tumors are often associated with the migration ofmalignant cells to adjacent, otherwise healthy areas of the brain. Thisoften results in a primary tumor surrounded by multiple microscopictumors that cannot be imaged to permit surgical resection and thuscannot be easily detected for removal. The effectiveness of radiationand chemotheropy are significantly hindered by the unique anatomy of thecentral nervous system. Even with such treatment, the median survivaltime for GBM patients is about one year or less, and less than 2% ofpatients survive three years. This also further complicates the alreadydifficult task of maintaining the effectiveness of chemotherapy in theface of cancer's rapid adaptability.

Recent efforts have suggested that external electrode therapy canimprove the prognosis of GBM patients. The malignancy of cancer isattributable to uncontrolled cell proliferation, which is largelymediated by interactions between highly charged molecules. Recently,application of electric fields to the scalp has been used disruptinteractions among charged molecules, which reduces cancerproliferation.

However, these efforts have demonstrated limited efficacy due to therestrictions imposed by applying electrodes to the skin. By directingthe electric fields a distance through the skull and soft tissue, thestrength of the field applied to the cancerous cells is dampened. A needexists, therefore, to optimize the strength and specificity of the fieldthat is applied to the cancerous cells. This need applies not only toGBM but to all tumor types where adjacent, healthy tissue could bedamaged by conventional treatments.

SUMMARY

The present disclosure provides advantages over existing standard ofcare treatments for cancer by providing the effectiveness of amulti-drug regimen without the toxicity associated with pharmaceuticaltreatments. Additionally, implantation of the leads is minimallyinvasive, providing advantages over surgical resection. Thus, thepresent disclosure provides for a cancer treatment both more effectiveand with less damaging collateral effects than existing treatments.

Embodiments of the present disclosure include DBS systems and methodsfor delivering electric fields directly to a tumor for treatment ofvarious cancers, such as GBM. The disclosed systems and methods producea range of stimulation settings that can impede or stop cell growth fora plurality of tumor types. In embodiments, target objectives caninclude mitosis inhibition, immune suppression, and inhibition of DNAreplication processes, all of which can halt growth of cancerous cells.Embodiments may act as an electromagnetic (EM) analog to a multi-drug,and combine target objectives in parallel, sequence, or a cycle to meetthe rapid adaption of cancer cells to a particular mode of inhibition.

A method for programming a signal generator with a DBS lead configuredto deliver stimulation to a tumor is disclosed. The method can comprisegenerating a tumor profile based on one or more characteristics of thetumor, generating one or more electrode configurations and one or moresets of stimulation settings based on the tumor profile, and providing,to a signal generator, the selected sets of stimulation settings.

The tumor profile can be acquired by using an imaging modality tocapture the tumor and then generating a tumor profile based on theimaging data. The profile can then be used to select electrodeconfigurations to create a desired Volume of Tissue Activation (VTA),which can be customizable to each patient's unique tumor. Thestimulation delivered by the selected electrodes can be applied based ona set of stimulation settings. Electrode configurations and stimulationsettings can be selected by a computer algorithm based on the desiredeffect on the tumor. Various sets of stimulation settings can be used inorder to provide optimal treatment to the patient. Sets of stimulationsettings can be selected based on the specific cell process that istargeted. For example, stimulation settings may be selected to targetinhibition of mitosis, immune suppression, or inhibition of DNAreplication. Computer algorithms can be used to select the electrodeconfiguration and stimulation settings for each individual patient.Furthermore, various sets of stimulation settings may be deliveredsimultaneously, cyclically, asynchronously/independently, or in analternating fashion.

A system comprising an algorithm according to which one or more tumorcharacteristics are utilized to select stimulation settings intended todisrupt tumor cell growth processes is disclosed. The system comprises asignal generator coupled to one or more leads configured to be implantedsuch that the generated electric field is applied directly within atumor. The leads comprise one or more electrodes, which are configuredto produce an optimal electric field/VTA based on the desired effect onthe tumor. The system further comprises a programmer in communicationwith the signal generator and configured to deliver stimulation to theelectrodes according to the selected stimulation parameters.

The system can select the desired electrode configuration from a set ofreadily available leads, or it can design custom electrodeconfigurations based on the desired effects on the tumor. The systemalso can apply various sets of stimulation settings to the tumor via theelectrode configuration. When more than one set of settings is selected,the system can apply the sets of settings simultaneously, cyclically,asynchronously/independently, or in an alternating fashion. The systemcan also select stimulation settings based on the specific cell processthat is targeted. For example, the system may select stimulationparameters to target mitosis, immune suppression, prevention ofinflammation, or inhibition of DNA replication, among others.

The above summary is not intended to describe each illustratedembodiment or every implementation of the subject matter hereof. Thefigures and the detailed description that follow more particularlyexemplify various embodiments.

BRIEF DESCRIPTION OF THE DRAWINGS

The Subject matter hereof may be more completely understood inconsideration of the following detailed description of variousembodiments in connection with the accompanying figures, in which:

FIG. 1 is an example waveform that can be used for treatment of a tumor,according to an embodiment.

FIG. 2A is a simplified schematic of an electrode pair, according to anembodiment.

FIG. 2B depicts test data corresponding to treatment of a tumor by anembodiment.

FIG. 2C is a side view of an electrode pair according to an embodiment.

FIG. 2D depicts test data corresponding to treatment of a tumor by anembodiment.

FIG. 3A depicts test data corresponding to treatment of tumor cellsaccording to an embodiment.

FIG. 3B is an example decay curve depicting the multi-drug-analogoustreatment model, according to an embodiment.

FIG. 4A is a schematic side view depicting a lead implanted in the tumorof a patient according to an embodiment.

FIG. 4B is a schematic side view depicting two leads implanted in thetumor of a patient according to an embodiment.

FIG. 4C depicts customized leads for tumor ablation according to twoembodiments.

FIG. 5A is a schematic view depicting a lead with four electrodes, andthe electric field/VTA produced by the configuration, according to anembodiment.

FIG. 5B is a schematic view depicting a lead with eight electrodes, andthe electric field/VTA produced by the configuration, according to anembodiment.

FIG. 5C is a schematic view depicting a lead with a custom electrodearrangement, and the electric field/VTA produced by the configuration,according to an embodiment.

FIG. 6 is a block diagram of an imaging, treatment design, and signalgeneration system according to an embodiment.

FIG. 7A is a flowchart of a method for performing direct electrodestimulation of cancerous tissue in a patient, according to anembodiment.

FIG. 7B is a flowchart of a method for performing multi-drug-analogoustreatment using electromagnetic field, according to an embodiment.

FIGS. 8A and 8B depict a venous tumor trap, according to an embodiment.

Various features and elements discussed herein are not necessarily drawnto scale, with some elements being enlarged in the drawings for thepurposes of illustration and to aid understanding. While variousembodiments are amenable to various modifications and alternative forms,specifics thereof have been shown by way of example in the drawings andwill be described in detail. It should be understood, however, that theintention is not to limit the claimed inventions to the particularembodiments described. On the contrary, the intention is to cover allmodifications, equivalents, and alternatives falling within the spiritand scope of the subject matter as defined by the claims.

DETAILED DESCRIPTION

Various embodiments described herein relate to treatment of cancers,including GBM, with electromagnetic therapy. The therapies describedherein do not require the administration of a pharmaceutical drug(though in some cases a medical practitioner may use these therapies inconjunction with pharmaceuticals), while still providing the benefits ofa multi-drug regimen.

I. Definitions

Various terms are used throughout this application that have specificdefinitions or are used in specific ways within the instant application.Among these are:

Minimally Invasive: surgery or other treatment designed to limit traumato the body of the patient, in particular to limit the size of incisionsneeded, minimizing the patient's pain, healing time, and subsequent riskof infection.

Non-Specific Electric Field: an electric field having a size and shapebased upon a tumor's 3-dimensional profile and type, which may spreadbeyond the tumor to include a surrounding area of healthy tissue.

Tumor Data: information regarding a tumor that is being treated, whichcan include (but is not limited to) one or more of tumor shape,location, density, size, or volume.

Electrical parameters: those parameters that can be used to set theoperation of electrodes described herein, which can include (but is notlimited to) amplitude, pulse width, frequency, waveform or pulse shape,pulse pattern, field orientation, or burst parameters.

Computing and other devices are discussed herein that can includememory. Memory can comprise volatile or non-volatile memory as requiredby the coupled computing device or processor to not only provide spaceto execute the instructions or algorithms, but to provide the space tostore the instructions themselves. In one embodiment, volatile memorycan include random access memory (RAM), dynamic random access memory(DRAM), or static random access memory (SRAM), for example. In oneembodiment, non-volatile memory can include read-only memory, flashmemory, ferroelectric RAM, hard disk, floppy disk, magnetic tape, oroptical disc storage, for example. The foregoing lists in no way limitthe type of memory that can be used, as these embodiments are given onlyby way of example and are not intended to limit the scope of thedisclosure.

In one embodiment, the system or components thereof can comprise orinclude various modules or engines, each of which is constructed,programmed, configured, or otherwise adapted to autonomously carry out afunction or set of functions. The term “engine” or “module” as usedherein is defined as a real-world device, component, or arrangement ofcomponents implemented using hardware, such as by an applicationspecific integrated circuit (ASIC) or field-10 programmable gate array(FPGA), for example, or as a combination of hardware and software, suchas by a microprocessor system and a set of program instructions thatadapt the engine to implement the particular functionality, which (whilebeing executed) transform the microprocessor system into aspecial-purpose device. An engine can also be implemented as acombination of the two, with certain functions facilitated by hardwarealone, and other functions facilitated by a combination of hardware andsoftware. In certain implementations, at least a portion, and in somecases, all, of an engine can be executed on the processor(s) of one ormore computing platforms that are made up of hardware (e.g., one or moreprocessors, data storage devices such as memory or drive storage,input/output facilities such as network interface devices, videodevices, keyboard, mouse or touchscreen devices, etc.) that execute anoperating system, system programs, and application programs, while alsoimplementing the engine using multitasking, multithreading, distributed(e.g., cluster, peer-peer, cloud, etc.) processing where appropriate, orother such techniques. Accordingly, each engine can be realized in avariety of physically realizable configurations, and should generallynot be limited to any particular implementation exemplified herein,unless such limitations are expressly called out. In addition, an enginecan itself be composed of more than one sub-engines, each of which canbe regarded as an engine in its own right. Moreover, in the embodimentsdescribed herein, each of the various engines corresponds to a definedautonomous functionality; however, it should be understood that in othercontemplated embodiments, each functionality can be distributed to morethan one engine. Likewise, in other contemplated embodiments, multipledefined functionalities may be implemented by a single engine thatperforms those multiple functions, possibly alongside other functions,or distributed differently among a set of engines than specificallyillustrated in the examples herein.

II. Electrical Field as Targeted Drug Substitute

As described above, the application of electromagnetic radiation, or theapplication of alternating current, are used in embodiments describedherein to provide an analog to a multi-drug treatment. In a conventionalmulti-drug treatment, a patient is given a drug that can reduce oreliminate a tumor. The tumor is monitored and, so long as the drug isstill effective, the treatment remains substantially unchanged. Once thetreatment begins to lose efficacy, however, a medical professional maymodify the drug or add some additional drug that operates in a differentway.

Similarly, the embodiments described herein provide electromagnetictreatment to destroy or reduce a tumor, and the various electricalparameters used in the treatments are analogous to the various drugsthat have been used conventionally. One type of electrical parameterinput may result in destruction of a tumor for a time, only to beginlosing efficacy later. The electrical parameters can be changedthroughout treatment in a similar fashion to pharmaceutical changes,with several key distinctions.

First, unlike a multi-drug treatment, the embodiments described hereincan be targeted to a precise area and the treatment itself can bemodified nearly instantaneously. Pharmaceuticals are typically deliveredvenously or orally, and in either case are delivered throughout thebody, which can have various adverse effects. Pharmaceuticals can alsocreate adverse interactions with other medications, and it may not bepossible to administer a desired treatment plan without changing othermedications or schedules. Furthermore, pharmaceuticals requirerelatively long time periods to take effect and, importantly, alsorequire significant time periods to wear off and leave the patient'ssystem, leaving no option for rapid response to changes in the tumorsbehavior by adjusting the pharmaceutical regimen. Though methodologiesexist to target pharmaceutical treatments to particular cells, theyoften require additional steps in the treatment and pose the samesystemic risks to the patient as the pharmaceuticals themselves.

For all these reasons, the conventional, pharmaceutical approach totumor reduction is not ideal. Although medical practitioners recognizethe benefit of rapidly changing treatment for cancers, none havepreviously proposed the solution described herein, which provideslocalized and rapidly changeable electromagnetic treatment to a tumor.

FIG. 1 is a graph of voltage over time for a hypothetical treatmentplan. FIG. 1 includes six separate treatment regions (R1-R6), each ofwhich corresponds to a different set of electrical parameters. R1 is atreatment region in which a sine wave signal is provided, R2 is atreatment region corresponding to a sawtooth wave, R3 is a treatmentregion corresponding to a square wave, R4 is a treatment regioncorresponding to a series of pulses, R5 is a treatment regioncorresponding to a constant voltage, and R6 is a treatment region thatcorresponds to a combination of both a constant voltage and a sine wave.Notably, in each region the electrical parameters in addition to waveshape vary, such as frequency and amplitude. Adjusting these parameterscan have various effects on the cells of the patients bode and thecancer. For example, increases in voltage and pulse width are known toalter membrane potentials and increase the permeability of cells.

III. Deep Brain Stimulators Case Study

DBS has been approved by the Food and Drug Administration (FDA) fortreatment of neuro-degenerative diseases, such as Parkinson's disease.Furthermore, the safety of implantation of electrodes, even long-term,for DBS is well established. This being said, electrode design andelectric fields required to disrupt cancer cell growth divergesignificantly from those used to treat neuro-degenerative diseases. Theneed exists, therefore, for a DBS device that utilizes an electrodeconfiguration and electric field configured specifically for thedisruption of the various processes of cell proliferation for treatmentof GBM. According to embodiments, an electric field can be applieddirectly to a tumor for disruption of one or more tumor proliferationprocesses.

Table 1 depicts example frequency ranges that target specific tumor orcellular processes. Electric fields with these or other frequency rangescan be delivered simultaneously, in an alternating fashion, or in acyclical manner in order to optimally disrupt the tumor cellproliferation processes.

TABLE 1 Frequency Range (Hz) Effect  61-200 Inhibit cellular mitosis300-700 Initiate immune suppression 1000+ Inhibit DNA processes

The examples in Table 1 are only some of the possible frequency rangesand effects, and others can be implemented in other to disrupt, inhibitor otherwise affect one or more particular or desired tumor cellularprocesses. For example, multiple frequencies can be deliveredsimultaneously to disrupt multiple processes all at once, or in apredefined pattern or in response to biological data. These frequenciesalso can be tuned to the patient's tumor characteristic or responsebehavior. In addition to modulating the intracellular processes withincancer cells, the electric field can modulate the content of the tumormicroenvironment, including recruitment of immune cells.

Electromagnetic fields may interfere with various cellular processes,depending on widely variable features of the field. For example, clearindicators and mechanisms have been identified to show disruption ofmitotic spindle formation by low frequency (e.g., <500 Hz) fields. Suchlow frequency fields interfere with the arrangement and stability ofmicrotubules, the tubular cytoskeletal polymers that form the mitoticspindle. Chemical anti-microtubule agents already see widespreadclinical use against multiple cancer types; however they carry the samerisks of damage to healthy tissue. The spindle is necessarily a dynamicstructure, due to its function of capturing and segregating chromosomesbetween daughter cells, and microtubules are inherently polar, resultingin mitotic spindles having distributed dipoles throughout theirstructure. Disrupting the arrangement of the microtubules causes thespindles to become increasingly fragile, resulting in the accumulationof mitotic defects in the progeny cells and/or cell cycle arrest of theparent at M phase. In many eukaryotic cells, even a relatively shortdelay in M phase may cause the cell to cease cycling and ultimatelytrigger an apoptosis pathway. The aneuploidy and polyploidycharacteristics accumulated through the cell line also lead to apoptosisthrough various pathways, especially if continual prevention of properspindle formation allows chromosomal errors to accumulate at a ratewhich prevents stabilization of the cell line by the cancer's alteredtumor suppressor activity.

Additionally, altering voltage and pulse width are known to altermembrane potential and increase cell permeability. Other parametersalter the characteristics of the field in other helpful ways, forinstance the amplitude of a particular signal factors into the size ofthe field generated.

Referring now to FIG. 2A, an example lead 102 is depicted. Lead 102 isconfigured with input regions 104 and output regions 106. Lead 102 isconfigured with 1:1 internal connection of the distinct input and outputchannels. That is, the lead electrodes and the stimulator can beconstructed and connected to allow for multiple independent control. Inthis way, each electrode can be independently configured to serve as ananode or a cathode, and each electrode could also deliver an independentset of treatment parameters. Each of the electrodes can deliver theirspecific stimulation therapy, independently, simultaneously, or ininterleaved patterns with respect to the other electrodes.

FIG. 2B depicts lead 102 in use in an in vitro environment. Plates 108,110, and 112 each depict a 10 cm cell culture dish with crystal violetstaining of tumor cells after a specific duration of electric fieldapplication via lead 102 (24 hours in this example, though the durationcan be different for other treatments). Crystal violet staining wasperformed thereafter. Control plate 108 was fitted with an electrodewithout an active electric field, with active electrode portions 114.Test plates 110 and 112 show the results of an active electrodedelivering waveforms at 100 Hz (plate 110) and 200 kHz (plate 112).Cleared zones 116 a and 116 b demonstrate tumor cell death in thevicinity of active electrode portions 114.

Referring now to FIG. 2C, an example lead 118 is depicted. Lead 118 isconfigured as a bipolar electrode enclosed in insulated tubing with onlythe tip 120 of the each of the positive electrode and negative electrodetouching the base of the plate 122. FIG. 2D depicts a top view of lead118 in use in an in vitro environment. Plates 124, 126, and 128 eachdepict a 35 mm cell culture dish showing crystal violet staining oftumor cells after a specific duration of electric field. Control plate124 is fitted with an electrode without an active electric field, withactive electrode portions 114. Test plates 126 and 128 show results ofan active electrode delivering waveforms at 100 Hz (plate 126) and 200kHz (plate 128). Cleared zones 116 c and 116 d demonstrate tumor celldeath in the vicinity of active electrode portions 114.

For the data shown in FIGS. 2D, a temperature sensor probe was used torecord the rise in temperature of the culture media, if any, between thetwo electrodes. The temperature was recorded between the two electrodesafter the delivery of electric field for a specific duration, and it wasfound that the temperature was of the order of 39.4 degrees C., which iswell within the physiological limit suggesting there is no non-specificthermal effect of electric field.

FIG. 3A depicts a graph 130 demonstrating progressive decrease in tumorcell counts over time after application of an electric field using lead118. Using a ratio of hand counted cells between a test plate and acontrol plate, the steady decrease in the test plate count leads to amarked decline in the ratio over 24 hrs. The ratio declines sharply overthe first six hours or so, before gradually appearing to level outroughly between the 18 and 24 hour mark, exemplifying the tendency, andcapacity, of tumor cells to mutate immunities to therapeutic methods.

FIG. 3B shows an example graph 132 of application of the methods andsystems of the present disclosure using a “multi-drug” methodology.Section 134 a follows approximately the same model as graph 130 of FIG.3A. When the decline in tumor size plateaus, the parameters of theapplied electronic field may be adjusted to drive further recession ofthe tumor, demonstrated in segment 134 b. This may be repeatediteratively until no further tumor cells are detected, demonstrated insegment 134 c.

Electrical stimulation can initiate a process of cell death and disruptcancer cell growth, which can inhibit tumor growth. Micrographs of cellsapproximately 24 hours after application of electric stimulationdelivered according to the systems and methods discussed herein showdecreased density of cells in comparison to the control samples whenstained with crystal violet, which demonstrates that there is a processof cell death that initiates after electric stimulation. Micrographs ofcells 48 hours after electric stimulation, when stained with crystalviolet, show almost no viable adherent tumor cells in comparison to thecontrol samples, which further demonstrates that a process of cell deathinitiates after electric stimulation. Micrographs of cells 48 hoursafter electric stimulation, when stained with crystal violet, showalmost no viable adherent tumor cells in comparison to the controlsamples, which further demonstrates that a process of cell deathinitiates after electric stimulation.

FIG. 4A depicts an example of a DBS system 200 for disruption of tumorproliferation processes. DBS system 200 includes at least one lead 202comprising one or more electrodes 204. Generally, the exterior surfaceof lead 202 comprises a non-conductive material while each electrode 204comprises an electrically conductive material. For example, in oneembodiment lead 202 comprises a polyurethane sleeve, and electrode 204comprises platinum-iridium. Other suitable materials or combinations ofmaterials can be used for one or both of lead 202 and electrode 204 inother embodiments. Lead 202 is in electrical connection via an extension206 (e.g., a cord, cable, wire or other structure in some embodiments,or a wireless arrangement in other embodiments) to a signal generator208. In embodiments, signal generator 208 can be implanted or external.In other embodiments, DBS system 200 can comprise more than one lead202, directed to one or more tumors or areas of interest. The number ofleads may be determined according to the particular geometry anddistribution of the target tissue.

In operation, system 200 provides tumor-specific, therapeutic electricalsignals generated by signal generator 208 to create an electric fieldwithin and around a tumor 210 or other treatment area by lead 202 andelectrodes 204. The electric field can trigger metabolic pathways in thetumor or other tissue at a cellular level to provide a therapeuticeffect, as discussed in more detail herein. Interactions of the fieldwith charged particles of the cells of the tumor can both directlydamage the cellular structures of the tumor and assist the patient'srecovery.

Referring now to FIG. 4B, an alternative embodiment of system 200 isshown with a dual lead 203 configuration. FIG. 4B depicts leads 203A and203B implant adjacent and on either side of tumor 210. Leads 203A and203B are similar to leads 118 a and 118 b of FIG. 2C. Placing bilateralleads 203A and 203B to bookend tumor 210 allows for the electric fieldgenerated by leads 203 to be distributed across tumor 210.

Referring now to FIG. 4C, examples of custom leads to accommodateirregular tumor shapes is depicted. Tumors 250 a and 250 b each have aunique geometry, and each of leads 252, 254, and 256 are customized todirect an electromagnetic field over the particular geometry of eithertumor 250 a or 250 b. Lead 252 has electrodes 258 clustered at eitherend of the lead 252 to direct the field over the large lobes of tumor250 a. Tumor 250 b, on the other hand, can be treated as two connectedunits, 251 a and 251 b, to create a more conforming EM field over theirregular shape of tumor 250 b and limit any potential effects onhealthy tissue. Lead 254 has regularly spaced electrodes 260 to coverthe larger unit 251 a, and a second lead 256 provides coverage over thesecond unit 251 b.

Leads 202 and 203 can comprise various electrode configurations. FIG. 5Adepicts one electrode configuration in which lead 202 comprises fourcircumpolar electrodes 204 a-d. A lead with four circumpolar electrodes,such as the lead shown in FIG. 5A can produce a non-specific electricfield 212 that extends beyond tumor 210. Such non-specific fields may beparticularly advantageous in ensuring the elimination of any malignantcells which may have spread from the main tumor.

FIG. 5B depicts a single, triple, triple, single electrodeconfiguration. In this configuration, lead 202 comprises eightelectrodes (204 e-g): electrodes 204 e and 204 g are circumpolar(“single”) electrodes, and electrodes 204 f are two rows of threeelectrodes (“triple”) surrounding the lead (only two electrodes of eachrow are visible in FIG. 5B). As depicted in FIG. 5B, a single, triple,triple, single electrode configuration can produce a non-specificelectric field 212 that is contoured to tumor 210. Contouring the fieldmay assist in focusing effects on a particular tumor or tumor region andmay be advantageous in embodiments used in regions of the body outsidethe central nervous system. Since cells in other systems generallydivide with greater frequency than mature neurons, embodiments designedfor applications in other systems may use field contouring to limit therisk of adverse effects on healthy tissue.

FIG. 5C depicts another electrode configuration in which lead 202comprises an array of electrodes 204 h arranged in multiple rows aroundlead 202. As depicted in FIG. 5C, the array of electrodes arranged inmultiple rows around lead 202 can produce an electric field thatconforms specifically to a boundary of tumor 210. Such conformation is amore precise version of the contouring discussed in regard to FIG. 5B,and carries many of the same advantages. For instance, for tumors of thegastrointestinal (GI) system, where the turnover of healthy cells isrelatively high, such a precisely conforming field would permittreatment of a tumor without damaging the patient's healthy GI tissueand therefore avoiding digestive complications.

FIGS. 5A-5C are only some examples of suitable lead configurations andelectric fields. Other configurations, arrangements and types of leadsthat produce other electric fields can be used in various embodimentsdiscussed herein. Leads may be prefabricated or assembled according tothe determined configuration using prefabricated or customizedelectrodes. Customization of leads and/or electrodes may vary inexecution, from assembling existing electrodes into a customized lead,implanting customized electrodes into an existing lead assembly, orfully fabricating a complete custom lead and electrode assembly, forexample through the use of 3D printing.

Custom contacts of lead 202 and electrodes 204 can be of varying shapeand distance from each other depending on the desired electricfield/VTA. Electrical parameters that can be customized include one ormore of amplitude, pulse width, frequency, waveform/pulse shape, pulsepattern, or burst. VTAs can also be shaped by preconditioning pulses orfield orientation.

In operation, lead 202 (and thereby electrodes 204) receives electricalsignals from signal generator 208 via extension 206 (see FIG. 4A). Inone embodiment, and referring to FIG. 6 , signal generator 208 comprisesa processor 232 and a memory 234. Memory 234 can include storage forstimulation settings 236, such as stimulation settings for eachelectrode 204 of lead 202.

Stimulation settings 236 can be generated by processor 232 or by anexternal source and can comprise, for example, an array, hash table,dictionary, database or other data structure keyed to each electrode204. In one example, stimulation settings 236 can define a modulated,pulsed signal that establishes an electric field in a tumor. Thestimulation settings can define a frequency (e.g., low, medium, high, orultra high), a pulse width or time, a pulse interval, a pulse pattern, apulse waveform shape (e.g., sine-type or square-wave pulse), a currenttype (e.g., AC vs. DC), a voltage, a power, or some other characteristicof a signal to establish a desired electric field.

Stimulation settings 236 can produce electrical signals that arecommunicated from signal generator 208 to lead 202 via extension 206 bycommunication engine 238, which can comprise wired or wirelesscommunication circuitry. In embodiments in which stimulation settings236 are at least partially formulated external to signal generator 208,communication engine 238 can receive stimulation settings 236 storedwithin memory 236, or alternatively can receive similar information andsettings directly from a programmer 222. In still other embodiments,signal generator 208 and programmer 222 can comprise an integrated unit.

Programmer 222 comprises, among other components appreciated by thoseskilled in the art, a lead data engine 226, an electric field dataengine 227, a tumor geometry engine 228 and a user interface engine 230.Programmer 222 can be a handheld device, laptop or desktop computer,server, tablet, cellular or smart phone or other computing devicecapable of data communication with signal generator 208. Lead dataengine 226 is configured to obtain or formulate data related to lead202, such as a particular configuration of electrodes 204. Electricfield data engine 227 is configured to obtain or formulate data relatedto electrical signals to be generated and provided to lead 202, such asa particular set of signal characteristics tailored for a particulartumor. In combination, the particular configuration of electrodes 204and electrical signals provided to lead 202 (and thereby electrodes 204)produce a desired electrical field to be applied to a tumor or othertarget tissue when lead 202 is implanted in the tumor or other targettissue.

Both lead data engine 226 and electric field data engine 227 can rely ondata from tumor geometry and density engine 228, which is configured togenerate or obtain data related to a tumor or tissue to be treated. Inone embodiment, tumor geometry engine 228 receives, via wired orwireless communications, tumor data from an imagine data engine 220.This data can be, for example, three-dimensional magnetic resonanceimaging (3D MRI) data, though in other embodiments other data can beused, such as two-dimensional MRI data or three- or two-dimensional datafrom another imaging modality (e.g., a computed tomography, or CT, scan,or a position emission tomography, or PET, scan, among other possiblymodalities). Imaging data obtained or provided by imaging data engine220 can be used by programmer 222 (or signal generator 208) to design atumor-specific electric field to be produced by signals generated bysignal generator 208 and communicated to lead 202 and electrodes 204implanted within a tumor. In particular, imaging data can be used toidentify a target volume of tissue activation (VTA) such thatappropriate leads, electrodes and stimulation parameters can be designedand selected.

Engines 226, 227, 228 and 230 can comprise software, firmware, hardwareor combinations thereof and can comprise or be controlled, executed orcoupled by a processor or other computing device. In still otherembodiments, engines 226, 227, 228 and 230 can comprise differentfunctions, routines, algorithms or functional units of a processor orother device. Other components of the devices depicted in FIG. 6 ,including hardware and software components, can be included even if theyare specifically depicted.

FIG. 7A is a flowchart of a method by which an electrode configurationcan be selected and signal generator can be programmed to deliver aspecific set of stimulation parameters to the patient.

At 320, a tumor is scanned with an imaging data engine in order toacquire tumor data. In one embodiment, the tumor data comprisesinformation regarding one or more of tumor shape, location, density,size, or volume. At 322, the tumor data can be communicated to aprogrammer. The programmer can model the tumor via a tumor geometryengine. The programmer can then use electric field data engine to modelan electric field to be targeted to the tumor based on the tumor data.The programmer can utilize a lead data engine to design, model or selecta lead based on the electric field model. The configuration ofelectrodes on the lead, along with the signal provided according to theelectric field, will define the shape and other characteristics of theelectric field generated and delivered to the tumor.

At 324, a lead, as designed, modeled, or selected by the programmer, isobtained or constructed. Further, at 326, the signal generator isprogrammed by the programmer with stimulation settings based on themodeled electric field. The stimulation parameters define the intensityand dynamics of the electric field. Such parameters can be adjusted byprogrammer to disrupt the various processes of tumor cancer cell growth.

Accordingly, embodiments of the systems and methods herein can beconsidered to deliver a “multi-drug” that selectively targets one ormore processes of the tumor in a therapeutically beneficial way, therebyinhibiting tumor growth. If or as the tumor responds, the multi-drug canbe tuned (i.e., one or more characteristics of the lead, electrodes, orstimulation settings defining the electric field can be adjustedaccording to the tumor's response) accordingly. The field can thus beprogrammed to proactively address the rapid desensitization that sometumors exhibit in the course of therapy, wherein a drug or regimen willabruptly cease to be effective due to mutation of the tumor genome. Byapplying a mixed-or cycling-effect field (or “multi-drug”), thepossibility of a mutation arising in the tumor which may permit it tosurvive the treatment, as any mutation that renders the tumor resistantto a particular effect of the field will likely leave it vulnerable toother effects.

For example, a tumor may initially be treated with a low frequencywaveform to interfere with the stability of mitotic division. If thetumor fails to respond, or responds and then plateaus, the stimulationsetting may be adjusted to treat the tumor with a high frequencywaveform instead. In particular, tumors that are especially large,cross-sectionally diverse, or otherwise malignant may invite treatmentof mixed frequencies (or other features), either overlapping or cyclingas part of the initial stimulation pattern. In some situations, therecan be more than one combination of lead(s), electrodes and stimulationparameters that can result from the model (from which a user may selector according to which a preferred or optimized combination can berecommended), while in others a single optimized combination of lead(s),electrodes and stimulation parameters can result.

At 328, a lead is implanted directly adjacent to the tumor of interest,and the signal generator directs stimulation parameters to the lead.Implanting the lead directly adjacent to tumor provides severaladvantages, including being able to target the electric field directlyat and into the tissue of interest, which can minimize the potential foradverse effects on healthy tissue around the tumor. In some embodiments,electrical stimulation can be applied repeatedly in order to apply asequence or range of stimulation parameters that will disrupt targetedprocesses. This repetition can be close in time (e.g., spaced apart byseconds or minutes) or farther apart (e.g., repeated daily, weekly,monthly or according to some other period), or even simultaneously, orrandomly, to prevent accommodation or adaptation to the therapy andproduce a more robust effect.

In other embodiments, more or fewer activities can be carried out aspart of the method, such that additional activities not depicted in FIG.7A can be included, or activities that are depicted can be reordered oromitted. For instance, in the case of especially large brain tumors,treatment may begin with surgical resection to release cranial pressure,and lead implantation can occur concurrent or subsequent to theresection.

In various embodiments, embodiments of the devices and systems discussedherein can be used to obtain a three-dimensional model of a tumor orother target tissue, define a desired volume of tissue activation basedon the three-dimensional model, select an appropriate lead and electrodeconfiguration for the desired volume tissue activation, and a definecharacteristics of an electric field to be established by the lead andelectrode configuration when the lead is implanted within the tumor orother target tissue to deliver the electric field therein. After one ormore treatments, these activities can be repeated, with one or more ofthe lead, electrodes or electric field characteristics adjustedaccording to the particular response of the tumor or other tissue (whichcan be determined by re-imaging or using other techniques (e.g.,analyzing patient symptoms and correlating symptoms with imaging data toobtain a patient positive effect score) to characterize the tumor ortissue.

FIG. 7B shows flowchart 302 of a method for using the systems anddevices of the present disclosure for a “multi-drug” treatment regimen.At operation 330, an initial electrical stimulation is applied,according to the VTA determined from an initial scan. After treatment atthe initial stimulation setting has been completed for the determinedduration, the tumor is scanned again, as at operation 332. A new VTA iscalculated from the new scan and compared with the initial VTA, as atdecision block 334. If change is detected, the treatment is continuedaccording to the current settings, at operation 330.

However, if no change is detected, the tumor can be determined to beunresponsive to the current treatment, and the parameters of the fieldmay be altered, as at operation 336. Parameters may be altered to adjustthe mode of attack, e.g., by change the frequency, or intensity of thetreatment, e.g., by decreasing the pulsewidth. Once the new parametersare entered, treatment is resumed by the applying the electricalstimulation, at operation 330. Method 302 may continue iteratively untilthe tumor is sufficient reduced.

Thus, the systems and methods discussed herein can be considered to be a“smart multi-drug” that can be used to target and treat various tumorsand tissues and selectively adapt according to a particular effectdesired or actual response of the tumor or tissue. Such smartmulti-drugs can be used to treat a variety of tumors and cancers as wellas other conditions (e.g., inflammation). The particular conditions,frequencies, and other characteristics given herein are merely examplesof some possibilities and are not limiting with respect to theapplicability of various contemplated embodiments.

For instance, the example and embodiments discussed herein are largelydirected to treatment in particular of GBM in the brain. However, otherembodiments follow naturally from the technology described herein.Tumors of the spinal cord, which do not permit direct implantation ofelectrodes due to the narrow confines of the spinal column, could betreated with epidural leads. Melanoma and other cancers of the skincould be treated with such epidural leads as well. Osteosarcoma andother bone tumors could be treated without the severe side effects ofradiation or systemic chemotherapy. Blood cancers could be treated withventricular filters fitted to deliver an electric field to passing bloodcells and thus attack tumors of the blood.

Referring now to FIG. 8A, an alternative embodiment demonstrating theuse of an epidural lead 410 to treat a spinal tumor 412 is depicted.Though the narrow confines of the spinal column make implantation intothe spine difficult, a lead implanted adjacent to the spine is able toproject a field 414 across the tumor in the spine to effect treatment.

FIG. 8B depicts an alternative embodiment demonstrating use of venousfilter 416 to project filed 418 and capture blood tumor 420 for exposureto the field. Venous filter 416 can have attached leads to project field418, or field 418 may be projected by leads implanted in adjacentepidural or other tissue. Venous filter 416 captures blood cancer tumor420 and retains the tumor 420 within the field 418 to effect treatment.

Various embodiments of systems, devices, and methods have been describedherein. These embodiments are given only by way of example and are notintended to limit the scope of the claimed inventions. It should beappreciated, moreover, that the various features of the embodiments thathave been described may be combined in various ways to produce numerousadditional embodiments. Moreover, while various materials, dimensions,shapes, configurations and locations, etc. have been described for usewith disclosed embodiments, others besides those disclosed may beutilized without exceeding the scope of the claimed inventions.

Persons of ordinary skill in the relevant arts will recognize that thesubject matter hereof may comprise fewer features than illustrated inany individual embodiment described above. The embodiments describedherein are not meant to be an exhaustive presentation of the ways inwhich the various features of the subject matter hereof may be combined.Accordingly, the embodiments are not mutually exclusive combinations offeatures; rather, the various embodiments can comprise a combination ofdifferent individual features selected from different individualembodiments, as understood by persons of ordinary skill in the art.Moreover, elements described with respect to one embodiment can beimplemented in other embodiments even when not described in suchembodiments unless otherwise noted.

IV. Discussion of Specific Claimed Embodiments

In one embodiment, a signal generator is electronically coupled to aplurality of electrodes. The signal generator comprises a processorconfigured to receive a set of tumor-specific electromagnetic field dataand generate a corresponding set of stimulation settings, wherein theset of stimulation settings comprise a specific output setting for eachof the plurality of electrodes; a memory configured to receive and storethe set of stimulation settings from the processor; and a communicationengine configured to deliver the specific output settings to eachcorresponding one of the plurality of electrodes to generate atumor-specific electromagnetic field based upon to the tumor-specificelectromagnetic field data. The specific output settings include a setof electrical parameters based upon the tumor-specific electromagneticfield data.

The processor may be configured to receive the tumor-specific field datafrom a programmer module and generate the set of stimulation settingsbased on a tumor profile and a desired effect on the tumor. The tumorprofile may be produced based on a tumor type and a three-dimensionalmodel of the tumor. The programmer module may in fact be a part of thesignal generator itself. The processor may be configured to receive oneor more electrode configurations. The the one or more electrodeconfigurations may be received from a programmer module and based on atumor profile and a desired effect on the tumor. The one or moreelectrode configurations comprise an array of the plurality ofelectrodes on an implantation lead. The one or more electrodeconfigurations may be selected from readily available implantation leadsbased on the profile and a desired effect on the tumor. The implantationlead may configured for implantation in a brain of a patient. Theimplantation lead may be configured for epidural implantation. The leadmay be integrated with a venous filter. The one or more electrodeconfigurations may be customized based on the profile and a desiredeffect on the tumor. The implantation lead may include one of the one ormore electrode configurations and can be generated through 3D printingor other additive or custom manufacturing processes. The one or moreelectrode configurations can be obtained using a computer-implementedalgorithm. The electrode configuration can include two or moreelectrodes and each of the two or more electrodes is stimulated with adifferent one or more of the one or more stimulation settings. The oneor more sets of stimulation settings can be obtained using acomputer-implemented algorithm, which can include machine-learning orneural network based algorithms. The one or more sets of stimulationsettings can be delivered simultaneously or sequentially. The one ormore sets of stimulation settings can be delivered cyclically orrandomly. The one or more sets of stimulation settings can be deliveredby alternating among the one or more sets of stimulation settings. Afirst set of the one or more sets of stimulation settings may targetsmitosis inhibition, wherein one of the stimulation parameters includedin the first set is frequency, and wherein the frequency is in a rangeof 61 Hz to 200 Hz. A second set of the one or more sets of stimulationsettings may target immune suppression, wherein one of the stimulationparameters included in the second set is frequency, and wherein thefrequency is in a range of 300 Hz to 700 Hz. A third set of the one ormore sets of stimulation settings can target inhibition of DNAreplication, wherein one of the stimulation parameters included in thethird set is frequency, and wherein the frequency is equal to or greaterthan 1,000 Hz. The processor can be further configured to receive asecond set of tumor-specific electromagnetic field data and generate asecond corresponding set of stimulation settings. The second set oftumor-specific electromagnetic field data can be based on a first tumorprofile, a second tumor profile, and a rate of change of the of thetumor profile based on the first tumor profile and the second tumorprofile.

It should be understood that many of these features are interoperablewith one another. For example, using different sets of inhibitionwaveforms sequentially or simultaneously are interoperable features.

According to another claimed embodiment, an electrical stimulationsystem comprises a programmer module configured to receive imaging datafor a target tissue and to generate a profile of the target tissue,wherein the programmer module is configured to generate one or more setsof stimulation settings based on the profile and a desired volume oftissue activation (VTA) of the target tissue; a signal generatorconfigured to generate electrical stimulation signals according to theone or more sets of stimulation settings; and one or more leads eachcomprising one or more electrodes, the one or more deep brainstimulation leads electrically coupled with the signal generator toreceive the electrical stimulation signals and to apply an electricfield to the target tissue when implanted within the target tissue.

In embodiments, each of the one or more leads is a deep brainstimulation lead. Each of the one or more leads may be a epiduralimplantation lead. Each of the one or more leads may be integrated witha venous filter. The programmer module may be configured to generate anelectric field model based on the profile and the desired VTA of thetarget tissue, and the programmer module may use the electric fieldmodel to generate the one or more sets of stimulation settings. Theprogrammer module may generate one or more configurations of the one ormore electrodes on the one or more leads based on the electric fieldmodel. The programmer may selects the one or more configurations from aset of available leads. The programmer module can select a customelectrode configuration. The signal generator can deliver the one ormore sets of stimulation settings simultaneously, cyclically, orrandomly. The signal generator can deliver the one or more sets ofstimulation settings by alternating the one or more sets of stimulationsettings. The programmer module can receive a second set of imaging datafor the target tissue after the electric field is applied to the targettissue and in response the programmer module generates a second profileof the target tissue and a second one or more sets of stimulationsettings based on the second set of imaging data and a correspondingdesired VTA.

As described previously, these features are interoperable with oneanother, and a skilled person would recognize that they can be combinedin various combinations and permutations.

According to another embodiment, a signal generator comprises aprocessor. The processor is configured to produce an output based upon afirst set of electrical parameters corresponding to a first cell cellproliferation process; receive tumor image data; determine whether thetumor image data is indicative of minimal change in Volume of TumorActivation (VTA) over time; and, in response to the determination thatthe tumor image data is indicative of minimal change in VTA, produce anoutput based upon a second set of electrical parameters corresponding toa second cell proliferation process.

The signal generator further include an electrode, the electrodeconfigured to deliver an electromagnetic signal to a tumor based uponthe first set of electrical parameters and upon the second set ofelectrical parameters.

Although a dependent claim may refer in the claims to a specificcombination with one or more other claims, other embodiments can alsoinclude a combination of the dependent claim with the subject matter ofeach other dependent claim or a combination of one or more features withother dependent or independent claims. Such combinations are proposedherein unless it is stated that a specific combination is not intended.

Any incorporation by reference of documents above is limited such thatno subject matter is incorporated that is contrary to the explicitdisclosure herein. Any incorporation by reference of documents above isfurther limited such that no claims included in the documents areincorporated by reference herein. Any incorporation by reference ofdocuments above is yet further limited such that any definitionsprovided in the documents are not incorporated by reference hereinunless expressly included herein.

For purposes of interpreting the claims, it is expressly intended thatthe provisions of 35 U.S.C. § 112(f) are not to be invoked unless thespecific terms “means for” or “step for” are recited in a claim.

1-38. (canceled)
 39. A signal generator comprising a processor, wherein the processor is configured to: produce an output based upon a first set of electrical parameters corresponding to a first cell proliferation process; receive tumor image data; determine whether the tumor image data is indicative of minimal change in Volume of Tumor Activation (VTA) over time; and in response to the determination that the tumor image data is indicative of minimal change in VTA, produce an output based upon a second set of electrical parameters corresponding to a second cell proliferation process.
 40. The signal generator of claim 39, further comprising an electrode, the electrode configured to deliver an electromagnetic signal to a tumor based upon the first set of electrical parameters and upon the second set of electrical parameters.
 41. The signal generator of claim 40, wherein the output comprises an electrode configuration.
 42. The signal generator of claim 41, wherein the electrode configuration is based on an initial VTA and at least one of the first cell proliferation process and the second cell proliferation process.
 43. The signal generator of claim 41, wherein the processor generates: a tumor profile based on at least the tumor image data; a target VTA based on the tumor profile and the tumor image data: and the electrode configuration based on the tumor profile and the target VTA.
 44. The signal generator of claim 43, wherein the processor further determines, based on the target VTA, one or more preconditioned pulses or a field orientation.
 45. The signal generator of claim 41, wherein the electrode configuration comprises assembling one or more electrodes into a lead.
 46. The signal generator of claim 45, wherein the one or more electrodes are prefabricated electrodes.
 47. The signal generator of claim 45, wherein at least one of the one or more electrodes is a customized electrode.
 48. The signal generator of claim 45, wherein the lead is a prefabricated lead.
 49. The signal generator of claim 45, wherein the lead is a customized lead.
 50. The signal generator of claim 41, wherein the electrode configuration comprises an electrode shape.
 51. The signal generator of claim 41, wherein the electrode configuration comprises a distance between two or more electrodes.
 52. The signal generator of claim 39, wherein the first set of electrical parameters and the second set of electrical parameters each comprises one or more of an amplitude, a pulse width, a frequency, a waveform, a pulse shape, a pulse pattern, or a burst.
 53. A method of optimizing a lead in a signal generator system, the method comprising: receiving tumor image data; determining a tumor profile based on at least the tumor image data; determining a target VTA based on the tumor profile and the tumor image data; generating an electric field model based on the tumor profile and the target VTA; and generating an electrode configuration configured to generate an electric field consistent with the electric field model.
 54. A system for optimizing a lead for a signal generator, the system comprising a programmer module configured to: receive tumor image data; determine a tumor profile based on at least the tumor image data; generate tumor specific field data based on the tumor image data; generate an electrode configuration based on the tumor profile and a target effect on the tumor; generate a set of stimulation settings, for the electrode configuration, corresponding to the tumor-specific field data.
 55. The system of claim 54, wherein the electrode configuration comprises an array of one or more electrodes on an implantation lead.
 56. The system of claim 55, wherein at least one of the one or more electrodes is a customized electrode.
 57. The system of claim 54, wherein the electrode configuration comprises one or more of an electrode shape and a distance between two or more electrodes.
 56. The system of claim 54, wherein the set of stimulation settings comprises, based on the target VTA, one or more preconditioned pulses or a field orientation.
 59. The system of claim 54, wherein the set of stimulation settings comprise one or more of an amplitude, a pulse width, a frequency, a waveform, a pulse shape, a pulse pattern, or a burst. 